Pharmaceutical complex

ABSTRACT

This invention relates to a complex of eletriptan and a sulphobutylether-beta-cyclodextrin, or a pharmaceutically acceptable salt thereof, and to processes for the preparation of, pharmaceutical formulations including, and the uses of, such a complex.

[0001] This application is a Divisional of U.S. Ser. No. 09/606,508filed Jun. 29, 2000, which claimed priority to United KingdomApplication No. 9915231.6 filed Jun. 29, 1999.

[0002] This invention relates to a complex of eletriptan and asulphobutylether-beta-cyclodextrin, or a pharmaceutically acceptablesalt thereof, and to processes for the preparation of, pharmaceuticalformulations including, and the uses of, such a complex.

[0003] Eletriptan,3-([1-methylpyrrolidin-2(R)-yl]methyl)-5-(2-phenylsulphonylethyl)-1H-indole, is disclosed in WO-A-92/06973. A preferred hydrobromide saltform of eletriptan is disclosed in WO-A-96/06842. WO-A-99/01135discloses a pharmaceutical formulation comprising eletriptanhemisulphate and caffeine. WO-A-00/06161 describes the use of eletriptanfor the prevention of migraine recurrence.

[0004] Eletriptan is a 5HT_(1B/1D) receptor agonist and has been shownto be highly effective for the treatment of migraine and the preventionof migraine recurrence. Eletriptan has also been disclosed for thetreatment of hypertension, emesis, depression, anxiety, an eatingdisorder, obesity, drug abuse, cluster headache, pain, chronicparoxysmal hemicrania and a headache associated with a vasculardisorder.

[0005] In order to administer eletriptan, or a salt thereof, by theintranasal route, it is desirable that a formulation does not produceunacceptable levels of effect, such as irritancy, on the nasal mucosae.It has been found that the formulations described in WO-A-99/01135comprising eletriptan hemisulphate and caffeine are irritant on thenasal mucosae.

[0006] Accordingly, it is an object of the present invention to providea well-tolerated pharmaceutical formulation of eletriptan, or a saltthereof, that is suitable for administration by the intranasal route.

[0007] It is further object of this invention to provide awell-tolerated, stable, aqueous, pharmaceutical formulation containingeletriptan, or a salt thereof, that is suitable for parenteral,preferably, intranasal administration and which enables the drug to havegood bioavailability and rapid onset of action.

[0008] WO-A-91/11172 and WO-A-94/02518 disclose sulphoalkyl ethercyclodextrin derivatives.

[0009] WO-A-98/02186 discloses an inclusion complex of (a) an indoleselective serotonin (5-HT_(1D)) agonist or a pharmaceutically acceptablesalt thereof and (b) an unsubstituted or substituted beta- orgamma-cyclodextrin, together with pharmaceutical compositions thereof.

[0010] It has now been found that eletriptan, or a salt thereof, canform a complex with certain sulphobutylether-beta-cyclodextrinderivatives of the type disclosed in WO-A-91/11172. Although thiscomplexation undesirably and unpredictably decreases the aqueoussolubility of eletriptan, or a salt thereof, it unexpectedly andadvantageously provides a complex which is well-tolerated whenadministered intranasally, principally since it has a negligibleirritant effect on the nasal mucosae in comparison with both the knowncaffeine formulations of eletriptan disclosed in WO-A-99/01135 and othercyclodextrin complexes of eletriptan.

[0011] Accordingly, the present invention provides a complex ofeletriptan and a cyclodextrin derivative of the formula (I):

[0012] wherein

[0013] R^(1a-g), R^(2a-9) and R^(3a-9) each independently represent —OHor —O(CH₂)₄SO₃H;

[0014] provided that at least one of R^(1a-9) represents —O(CH₂)₄SO₃H:

[0015] or a pharmaceutically acceptable salt thereof.

[0016] Pharmaceutically acceptable salts of particular interestassociated with the eletriptan component are acid addition and basesalts thereof. Suitable acid addition salts are formed from acids whichform non-toxic salts and examples are the hydrochloride, hydrobromide,hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogenphosphate, acetate, maleate, fumarate, lactate, tartrate, citrate,gluconate, succinate, saccharate, benzoate, methanesulphonate,ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoatesalts. Hydrobromide and sulphate, including hemisulphate, salts arepreferred. Suitable base salts are formed from bases which formnon-toxic salts and examples are the sodium, potassium, aluminium,calcium, magnesium, zinc and diethanolamine salts.

[0017] Pharmaceutically acceptable salts of particular interestassociated with the cyclodextrin ring component are base salts of the—O(CH₂)₄SO₃H groups, for example, alkali metal salts, such as sodiumsalts.

[0018] For a review on suitable salts see Berge et al, J. Pharm. Sci.,66, 1-19, 1977.

[0019] A pharmaceutically acceptable salt may readily be prepared bymixing together solutions of eletriptan, the cyclodextrin or thecomplex, and the desired acid or base, as appropriate. The salt mayprecipitate from solution and be collected by filtration or may berecovered by evaporation of the solvent. When a salt of eletriptanand/or the cyclodextrin are/is seperately prepared, these/this may thenbe used for the preparation of the complex.

[0020] A polymorph of eletriptan, or a salt thereof, may also be usedfor the purpose of the present invention.

[0021] Preferably, the average number of —O(CH₂)₄SO₃H groups permolecule of formula (I) is in the range of from 6.1 to 6.9, for example,6.5 or about 6.5.

[0022] It is preferred that each —O(CH₂)₄SO₃H present is in the form ofan alkali metal salt (such as the sodium salt).

[0023] Preferably, the molar ratio of eletriptan:cyclodextrin derivativeof the formula (I) is from 1:1 to 15:1, most preferably from 1:1 to10:1.

[0024] Preferably, eletriptan is present in the form of the hemisulphatesalt.

[0025] The complex can be administered alone but will generally beadministered in admixture with a pharmaceutically acceptable excipient,diluent or carrier selected with regard to the intended route ofadministration and standard pharmaceutical practice.

[0026] For example, the complex can be administered orally, buccally orsublingually in the form of tablets, capsules, ovules, elixirs,solutions or suspensions, which may contain flavouring or colouringagents, for immediate-, delayed-, sustained-, pulsed- orcontrolled-release applications.

[0027] Such tablets may contain excipients such as microcrystallinecellulose, lactose, sodium citrate, calcium carbonate, dibasic calciumphosphate and glycine, disintegrants such as starch (preferably corn,potato or tapioca starch), sodium starch glycollate, croscarmellosesodium and certain complex silicates, and granulation binders such aspolyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC),hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, stearic acid, glycerylbehenate and talc may be included.

[0028] Solid compositions of a similar type may also be employed asfillers in gelatin capsules. Preferred excipients in this regard includelactose, starch, a cellulose, milk sugar or a high molecular weightpolyethylene glycol. For aqueous suspensions and/or elixirs, the complexmay be combined with various sweetening or flavouring agents, colouringmatter or dyes, with emulsifying and/or suspending agents and withdiluents such as water, ethanol, propylene glycol and glycerin, andcombinations thereof.

[0029] The complex can also be administered parenterally, for example,intravenously, intra-arterially, intraperitoneally, intrathecally,intraventricularly, intrasternally, intracranially, intramuscularly orsubcutaneously, or it may be administered by infusion techniques. It isbest used in the form of a sterile aqueous solution which may containother substances, for example, enough salts or glucose to make thesolution isotonic with blood. The aqueous solutions should be suitablybuffered (preferably to a pH of from 3 to 9), if necessary. Thepreparation of suitable parenteral formulations under sterile conditionsis readily accomplished by standard pharmaceutical techniques well-knownto those skilled in the art.

[0030] For oral and parenteral administration to human patients, thedaily dosage level of eletriptan will usually be from 0.001 to 0.50mg/kg (in single or divided doses).

[0031] Thus tablets or capsules containing the complex may contain from5 to 240 mg of eletriptan, or a salt thereof, for administration singlyor two or more at a time, as appropriate. The physician in any eventwill determine the actual dosage which will be most suitable for anyindividual patient and it will vary with the age, weight and response ofthe particular patient. The above dosages are exemplary of the averagecase. There can, of course, be individual instances where higher orlower dosage ranges are merited and such are within the scope of thisinvention.

[0032] The complex can also be administered intranasally or byinhalation and is conveniently delivered as a single dose or multi-dosein the form of a dry powder inhaler or an aerosol spray presentationfrom a pressurised container, pump, atomiser, spray or nebuliser, withor without the use of a suitable propellant, e.g.dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, a hydrofluoroalkane such as1,1,1,2-tetrafluoroethane (HFA 134A [trade mark]) or1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbondioxide or other suitable gas. In the case of a pressurised aerosol, thedosage unit may be determined by providing a valve to deliver a meteredamount. The pressurised container, pump, atomiser, spray or nebulisermay contain a solution or suspension of the complex, e.g. using amixture of ethanol and the propellant as the solvent, which mayadditionally contain a lubricant, e.g. sorbitan trioleate. Capsules andcartridges (made, for example, from gelatin) for use in an inhaler orinsufflator may be formulated to contain a powder mix of the complex anda suitable powder base such as lactose or starch.

[0033] Aerosol or dry powder formulations are preferably arranged sothat each metered dose or “puff” contains from 1 to 16 mg of eletriptanfor delivery to the patient.

[0034] Alternatively, the complex can be administered in the form of asuppository or pessary, or it may be applied topically in the form of alotion, solution, cream, ointment or dusting powder. The complex mayalso be transdermally administered, for example, by the use of a skinpatch.

[0035] For application topically to the skin, the complex can beformulated as a suitable ointment containing the complex suspended ordissolved in, for example, a mixture with one or more of the following:mineral oil, liquid petrolatum, white petrolatum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, it can be formulated as a suitable lotion or cream,suspended or dissolved in, for example, a mixture of one or more of thefollowing: mineral oil, sorbitan monostearate, a polyethylene glycol,liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyidodecanol, benzyl alcohol and water.

[0036] The complex of the invention may be prepared from an aqueoussolution or slurry of eletriptan, or a salt thereof, and thecyclodextrin, or a salt thereof, by conventional methods. Where a solidcomplex is required, the solution or slurry may be dried by spray-dryingor freeze-drying (lyophilisation). Alternatively, eletriptan, or a saltthereof, and the cyclodextrin, or a salt thereof, can be mixed and thepowder mixture moistened with water. The mixture may then be vigorouslymixed to form a paste and dried at an elevated temperature, preferablyunder reduced pressure, to remove the water. The dried complex may becrushed and sieved to the desired particle size.

[0037] The solid complex can then be formulated for administration as apharmaceutical formulation by standard methods, for example, if anaqueous formulation is required the complex may be dissolved withstirring in water. A further suitable excipient, diluent or carrier maybe incorporated in the formulation at the blending or mixing step.Alternatively, a pharmaceutical formulation including the presentcomplex may be prepared by mixing eletriptan, or a salt thereof, and thecyclodextrin, or a salt thereof, together with a suitable excipient,diluent or carrier directly.

[0038] The complex can also be administered together with a prokinetic(e.g. metoclopramide) or antiemetic agent.

[0039] It is to be appreciated that all references herein to treatmentinclude curative, palliative and prophylactic treatment.

[0040] Preferably, the complex is administered as a pharmaceuticalformulation, most preferably, as an aqueous solution formulation.

[0041] Preferably, the pharmaceutical formulation is formulated forparenteral administration, for example, intranasal administration.

[0042] Preferably, a pharmaceutical formulation, most preferably, anaqueous pharmaceutical formulation, comprises one or more of thefollowing excipients, diluents or carriers:

[0043] (a) an anti-oxidant, for example, citric acid or ascorbic acid;

[0044] (b) a co-solvent, for example, ethanol, glycerol or a PEG200-400;and

[0045] (c) an organic polymer, for example, a water-soluble organicpolymer such as carboxymethylcellulose, polyvinylpyrrolidone orhydroxypropylmethyl cellulose.

[0046] The presence of an anti-oxidant increases the stability of theformulation.

[0047] The presence of an organic polymer or co-solvent optimises thebioavailability and increases the absorption and the onset of action ofeletriptan.

[0048] Preferably, the present invention provides a pharmaceuticalformulation, preferably an aqueous pharmaceutical formulation, includingfrom 10 to 150 mg/g of eletriptan or a salt thereof (preferably thehemisulphate), and from 10 to 30% weight/weight of thesulphobutylether-beta-cyclodextrin.

[0049] Preferably, up to and including 1% weight/weight of ananti-oxidant such as citric acid or ascorbic acid can be present.

[0050] Preferably, up to and including 30% weight/weight of a co-solventsuch as ethanol, glycerol or a PEG200-400, preferably glycerol, can bepresent.

[0051] Preferably, up to and including 0.5% weight/weight of an organicpolymer such as a water soluble polymer, for examplecarboxymethylcellulose, polyvinylpyrrolidone or hydroxypropylmethylcellulose, preferably carboxymethylcellulose or polyvinylpyrrolidone,can be present.

[0052] Preferably, from 10 to 150 mg/g of eletriptan hemisulphate ispresent.

[0053] Preferably, from 20 to 110 mg/g of eletriptan hemisulphate ispresent.

[0054] Preferably, from 50 to 120 mg/g of eletriptan hemisulphate ispresent.

[0055] Preferably, from 10 to 30% weight/weight of thesulphobutylether-beta-cyclodextrin is present.

[0056] Preferably, from 15 to 25% weight/weight of thesulphobutylether-beta-cyclodextrin is present.

[0057] Preferably, from 0.10 to 1.0% weight/weight of ascorbic acid ispresent.

[0058] Preferably, from 0.25 to 0.80% weight/weight of ascorbic acid ispresent.

[0059] Preferably, from 0.30 to 0.60% weight/weight of ascorbic acid ispresent.

[0060] Preferably, from 5.0 to 30.0% weight/weight of glycerol ispresent.

[0061] Preferably, from 10.0 to 25.0% weight/weight of glycerol ispresent.

[0062] Preferably, from 10.0 to 20.0% weight/weight of glycerol ispresent.

[0063] Preferably, from 0.05 to 0.5% weight/weight ofcarboxymethylcellulose or polyvinylpyrrolidone is present.

[0064] Preferably, from 0.05 to 0.2%, most preferably, from 0.1 to 0.2%,weight/weight of carboxymethylcellulose or polyvinylpyrrolidone ispresent.

[0065] Preferably, an aqueous pharmaceutical formulation is adjusted toa pH of from 4.0 to 9.0.

[0066] Preferably, an aqueous pharmaceutical formulation is adjusted toa pH of from 4.0 to 7.0.

[0067] Preferably, an aqueous pharmaceutical formulation is adjusted toa pH of from4.0to5.0.

[0068] The following Examples illustrate the preparation of aqueouspharmaceutical formulations including the complex of the presentinvention. The formulations were prepared by the addition of eletriptanhemisulphate, the sulphobutylether-beta-cyclodextrin, glycerol orpolyvinyl pyrrolidone, and ascorbic acid, to water (sufficient quantityto represent 80% of the final volume of the required formulation). Themixture was stirred to dissolve the solids and the resulting solutionadjusted to the required pH using 1 M aqueous sodium hydroxide solution.Water was then added to achieve the final volume required. Thesulphobutylether-beta-cyclodextrin used has an average sulphobutylethersubstitution of 6.5 per cyclodextrin molecule, and each sulphobutyletherunit was present as its sodium salt.

EXAMPLE 1

[0069] A formulation suitable for intranasal administration is anaqueous formulation comprising:

[0070] 100 mg/g of eletriptan hemisulphate;

[0071] 20% weight/weight of the sulphobutylether-beta-cyclodextrin;

[0072] 15% weight/weight of glycerol; and

[0073] 0.5% weight/weight of ascorbic acid:

[0074] with the formulation adjusted to from pH 4.0 to 5.0, preferablyabout pH 4.5, using aqueous sodium hydroxide solution.

EXAMPLE 2

[0075] A formulation suitable for intranasal administration is anaqueous formulation comprising:

[0076] 80 mg/g of eletriptan hemisulphate;

[0077] 20% weight/weight of the sulphobutylether-beta-cyclodextrin;

[0078] 0.15% weight/weight of polyvinylpyrrolidone; and

[0079] 0.5% weight/weight ascorbic acid:

[0080] with the composition adjusted to from pH 4.0 to 5.0, preferablyabout pH 4.5, using aqueous sodium hydroxide solution.

EXAMPLE 3

[0081] A formulation suitable for intranasal administration is anaqueous formulation comprising:

[0082] 80 mg/g of eletriptan hemisulphate;

[0083] 20% weight/weight of the sulphobutylether-beta-cyclodextrin;

[0084] 20% weight/weight of glycerol; and

[0085] 0.7% weight/weight of ascorbic acid:

[0086] with the formulation adjusted to from pH 4.0 to 5.0, preferablyabout pH 4.5, using aqueous sodium hydroxide solution.

EXAMPLE 4

[0087] A formulation suitable for intranasal administration is anaqueous formulation comprising:

[0088] 80 mg/g of eletriptan hemisulphate;

[0089] 20% weight/weight of the sulphobutylether-beta-cyclodextrin;

[0090] 0.10% weight/weight of polyvinylpyrrolidone; and

[0091] 0.7% weight/weight ascorbic acid:

[0092] with the composition adjusted to from pH 4.0 to 5.0, preferablyabout pH 4.5, using aqueous sodium hydroxide solution.

Biological Activity

[0093] The complex of the present invention may be tested for irritanteffects on the nasal mucosae by the following method.

[0094] Test solutions were prepared as follows:

[0095] (1) an aqueous solution containing 10% wt/wthydroxypropyl-beta-cyclodextrin (containing an average number ofhydroxypropyl groups per molecule of cyclodextrin of 0.6);

[0096] (2) an aqueous solution containing 17% wt/wt of the presentsulphobutylether-beta-cyclodextrin;

[0097] (3) an aqueous solution containing 10% wt/wthydroxypropyl-beta-cyclodextrin (containing an average number ofhydroxypropyl groups per molecule of cyclodextrin of 0.6) and 50 mg/mlof eletriptan hemisulphate; and

[0098] (4) an aqueous solution containing 17% wt/wt of the presentsulphobutylether-beta-cyclodextrin and 50 mg/ml of eletriptanhemisulphate.

[0099] All the above solutions were adjusted to pH 4.2±0.2.

[0100] Female Sprague-Dawley rats were used for the studies. The animalswere about 7 weeks old with a mean body weight of 199 g. Each study wasperformed on a group of five rats.

[0101] A 20 microlitre volume of the test solution was instilled intothe left nostril of each rat in the study group. The rats in each groupwere treated once daily with the same test solution for 7 days. The ratsin each study group were observed daily for mortality and clinicalsigns. They were weighed on study days—2, 1 and 7. On study day 8 therats were sacrificed and macroscopic and histopathological examinationswere carried out on the tissues of the respiratory tract only of eachrat.

[0102] No deaths were recorded. The results showed that test solutions(1), (2) and (4) did not produce any lesions. Test solution (3) inducedminimal to mild hyperplasia and metaplasia of the respiratory epitheliumand luminal exudate. These findings were interpreted as signs of minimalto mild irritation of the nasal turbinates.

[0103] It was concluded that test solution (4), containing a complex ofeletriptan hemisulphate and the presentsulphobutylether-beta-cyclodextrin, was non-irritant on the nasalmucosae when administered by the intranasal route.

1. A complex of eletriptan and a cyclodextrin derivative of formula (I):

wherein R^(1a-g), R^(2a-g) and R^(3a-g) each independently represent —OHor —O(CH₂)₄SO₃H; provided that at least one of R^(1a-9) represents—O(CH₂)₄SO₃H: or a pharmaceutically acceptable salt thereof.
 2. Acomplex according to claim 1, wherein the average number of —O(CH₂)₄SO₃Hgroups per molecule of the derivative of the formula (I) is in the rangeof from 6.1 to 6.9.
 3. A complex according to claim 1 wherein each—O(CH₂)₄SO₃H group present in the derivative of the formula (I) is inthe form of an alkali metal salt.
 4. A complex according to claim 1wherein the molar ratio of eletriptan:cyclodextrin derivative of theformula (I) is from 1:1 to 15:1.
 5. A complex according to claim 4wherein the molar ratio of eletriptan:cyclodextrin derivative of theformula (I) is from 1:1 to 10:1.
 6. A complex according to claim 1wherein eletriptan is present in the form of the hemisulphate salt.
 7. Apharmaceutical formulation including a complex according to claim 1 anda pharmaceutically acceptable excipient, diluent or carrier.
 8. Aformulation according to claim 7 wherein from 50 to 120 mg/g ofeletriptan hemisulphate is present.
 9. A formulation according to claim7 wherein from 15 to 25% weight/weight of thesulphobutylether-beta-cyclodextrin is present.
 10. A formulationaccording to claim 7, including one or more of an anti-oxidant, aco-solvent and an organic polymer.
 11. A formulation according to claim10 wherein the anti-oxidant is ascorbic acid.
 12. A formulationaccording to claim 11 wherein from 0.25 to 0.80% weight/weight ofascorbic acid is present.
 13. A formulation according to claim 10wherein the co-solvent is glycerol.
 14. A formulation according to claim13 wherein from 10.0 to 25.0% weight/weight of glycerol is present. 15.A formulation according to claim 10 wherein the organic polymer iscarboxymethylcellulose or polyvinylpyrrolidone.
 16. A formulationaccording to claim 15 wherein from 0.05 to 0.20% weight/weight ofcarboxymethylcellulose or polyvinylpyrrolidone is present.
 17. Aformulation according to claim 7 that is in the form of an aqueoussolution.
 18. An aqueous formulation according to claim 17 that has a pHof from 4.0 to 5.0.
 19. A formulation according to claim 7 which isadapted for parenteral administration.
 20. A formulation according toclaim 7 which is adapted for intranasal administration.
 21. Aformulation according to claim 7 which is adapted for inhalation.
 22. Aformulation according to claim 7 that is an aqueous solution comprising:80 mg/g of eletriptan hemisulphate; 20% weight/weight of thesulphobutylether-beta-cyclodextrin derivative of formula (I) having anaverage sulphobutylether substitution of 6.5 per cyclodextrin moleculewith each sulphobutylether unit present as its sodium salt; 20%weight/weight of glycerol; and 0.7% weight/weight of ascorbic acid: withthe formulation having been adjusted to from pH 4.0 to 5.0, preferablyabout pH 4.5, using aqueous sodium hydroxide solution.
 23. A formulationaccording to claim 7 that is an aqueous solution comprising: 80 mg/g ofeletriptan hemisulphate; 20% weight/weight of thesulphobutylether-beta-cyclodextrin derivative of formula (I) having anaverage sulphobutylether substitution of 6.5 per cyclodextrin moleculewith each sulphobutylether unit present as its sodium salt; 0.10%weight/weight of polyvinylpyrrolidone; and 0.7% weight/weight ascorbicacid: with the composition having been adjusted to from pH 4.0 to 5.0,preferably about pH 4.5, using aqueous sodium hydroxide solution.
 24. Amethod of treating in a mammal a disease for which a 5H_(1B/1D) receptoragonist is indicated including treating said mammal with an effectiveamount of a complex according to claim
 1. 25. A method of treating in amammal migraine or preventing migraine recurrence in a mammal includingtreating said mammal with an effective amount of a complex according toclaim
 1. 26. A process for the preparation of a complex according toclaim 1 which comprises combining eletriptan, or a pharmaceuticallyacceptable salt thereof, with the cyclodextrin derivative, or apharmaceutically acceptable salt thereof.
 27. A process for thepreparation of a formulation according to claim 7 which comprisescombining either (i) the complex comprising eletriptan and thecyclodextrin derivative of formula (I), or (ii) eletriptan, or apharmaceutically acceptable salt thereof, and the cyclodextrinderivative, or a pharmaceutically acceptable salt thereof, with apharmaceutically acceptable excipient, diluent or carrier.